Defective CD4(+)CD25(+) regulatory T cell functioning in collagen-induced arthritis: an important factor in pathogenesis, counter-regulated by endogenous IFN-gamma

Mice with a deficiency in IFN-gamma or IFN-gamma receptor (IFN-gamma R) are more susceptible to collagen-induced arthritis (CIA), an experimental autoimmune disease that relies on the use of complete Freund's adjuvant (CFA). Here we report that the heightened susceptibility of IFN-gamma R knock-out (KO) mice is associated with a functional impairment of CD4(+)CD25(+) T-reg cells. Treatment of wild-type mice with depleting anti-CD25 antibody after CFA-assisted immunisation with collagen type II (CII) significantly accelerated the onset of arthritis and increased the severity of CIA. This is an indication of a role of T-reg cells in the effector phase of CIA. IFN-gamma R deficiency did not affect the number of CD4(+)CD25(+) T cells in the central and peripheral lymphoid tissues. In addition, CD4(+)CD25(+) T cells isolated from naive IFN-gamma R KO mice had a normal potential to suppress T cell proliferation in vitro. However, after immunisation with CII in CFA, the suppressive activity of CD4(+)CD25(+) T cells became significantly more impaired in IFN-gamma R-deficient mice. Moreover, expression of the mRNA for Foxp3, a highly specific marker for T-reg cells, was lower. We further demonstrated that the effect of endogenous IFN-gamma, which accounts for more suppressive activity in wild-type mice, concerns both T-reg cells and accessory cells. Our results demonstrate that the decrease in T-reg cell activity in CIA is counter-regulated by endogenous IFN-gamma.